The long-term goal of our studies is to understand the molecular and genetic elements that underlie the process of aging and determine longevity. The aim of this proposal is to examine how mutations in a single gene, Indy, lead to a dramatic increase in life span in Drosophila melanogaster. We present data on the isolation and initial characterization of three independent P-element insertional mutations in the same gene, Indy, which cause a large increase in life span, and show that excision of the insert leads to reversion to a normal life span. The distribution of expression of the Indy gene, primarily in the fat body and oenocytes, and predicted sequence of the Indy protein, suggest that Indy may be playing a role in intermediary metabolism. The molecular and genetic analyses indicate that a partial reduction in the activity of this gene is responsible for an extension in life span, while a more severe reduction is detrimental to long life. The molecular, genetic, and physiological studies in this proposal will help provide an understanding of how an alteration in this single gene can lead to such a profound effect on increasing longevity.